The invention relates to methods of treating emphysema with 13-cis-retinoic acid, pharmaceutical compositions of 13-cis-retinoic acid useful in the treatment of emphysema and methods for delivering formulations of 13-cis-retinoic acid to the lung of a mammal suffering from emphysema.
Chemically, 13-cis-retinoic acid is (13Z)-retinoic acid and has the following structure: 
13-cis-retinoic acid is also known as isotretinoin, AGN 190013, Neovitamin A acid, Ro-4-3780, 13-cis-xcex2-Retinoic acid and 13-cis-Vitamin A acid. 13-cis-retinoic acid is sold under the tradenames Accutane(copyright), Roaccutan(copyright) and Roaccutane(copyright) for the treatment of severe recalcitrant nodular acne (Physicians"" Desk Reference 54th Ed., p. 2610, 2000; Peck et al., N. Eng. J. Med.; Peck et al., U.S. Pat. No. 5,698,593). 13-cis-Retinoic acid has also been reported to be effective in treating psychotic illnesses such as schizophrenia (Straw, U.S. Pat. No. 4,808,630) and cancer of head, neck and lung (Tomas et al., Annals of Oncology, 1999, 10, 95; Benner et al., Seminars in Hematology, 1994, 31, 26). 13-cis-Retinoic acid is currently in clinical trials for treatment of these forms of cancer at a number of locations (e.g., University of Texas SW Medical Center, Dallas Tex.; University of Texas MD Anderson Cancer Center, Houston, Tex.; Department of Veteran Affairs Medical Center, Temple, Tex.).
13-cis-retinoic acid is a member of the retinoid class of compounds which are structural analogues of vitamin A and include both natural and synthetic compounds. Naturally occurring retinoid compounds such as all trans retinoic acid (xe2x80x9cATRAxe2x80x9d), 9-cis-retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells.
For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of nuclear receptors that belong to the steroid/thyroid receptor superfamily. In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other medicinal applications of retinoids include the control of acute promyelocytic leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. However, retinoids often lack selectivity and consequently exert harmful pleiotrophic effects when used in therapeutically effective amounts, which may cause patient death. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, 9th edition (1996, McGraw-Hill) Chapters 63-64.
Chronic Obstructive Pulmonary Disease (xe2x80x9cCOPDxe2x80x9d) refers to a large group of lung diseases which prevent normal respiration. Approximately 11% of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States.
COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema.
Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow.
Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmful agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (i.e., by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained. At least four different types of emphysema have been described according to their locations in the secondary lobule: panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema
The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include but are not limited to chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema.
No effective methods for reversing the clinical indications of emphysema currently exist in the art. In some instances, medications such as bronchodilators, xcex2-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy.
Alveoli are formed during development by division of sacchules that constitute the gas-exchange elements of the immature lung. The precise mechanisms governing formation of septa and their spacing remain currently unknown in primates. Retinoids such as ATRA, which is a multifunctional modulator of cellular behavior that may alter both extracellular matrix metabolism and normal epithelial differentiation, have a critical regulatory role in mammals such as the rat. For example, ATRA modulates critical aspects of lung differentiation through binding to specific retinoic acid receptors that are selectively temporally and spatially expressed. Coordinated activation of different retinoic acid receptors subtypes has been associated with lung branching, alveolization/septation and gene activation of tropoelastin in neonatal rats.
During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls (Liu et al., Am. J. Physiol. 1993, 265, L430; McGowan et al., Am. J. Physiol., 1995, 269, L463) and retinoic acid receptor expression in the lung peaks (Ong et al., Proc. Natl. Acad. of Sci., 1976, 73, 3976; Grummer et al., Pediatr. Pulm. 1994, 17, 234). The deposition of new elastin matrix and septation parallels depletion of these retinoic acid storage granules. Postnatal administration of retinoic acid has been shown to increase the number of alveoli in rats, which supports the concept that ATRA may induces alveoli formation (Massaro et al., Am. J. Physiol., 270, L305, 1996). Treatment of newborn rat pups with dexamethasone, a glucocorticosteroid, prevents septation and decreases expression of some sub-types of retinoic acid receptor. Supplemental amounts of ATRA have been shown to prevent dexamethasone inhibition of alveoli formation. Further, ATRA prevents dexamethasone from diminishing retinoic acid receptor expression and subsequent alveolar septation in developing rat lung.
ATRA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema (Massaro et al., Nature Med., 1997, 3, 675; xe2x80x9cStrategies to Augment Alveolization,xe2x80x9d National Heart, Lung, and Blood Institute, RFA: HL-98-011, 1998; Massaro et al., U.S. Pat. No. 5,998,486). However, the mechanism of action of ATRA in these studies remains undefined, although Massaro reports that ATRA generates new alveoli. More importantly, the use of ATRA presents several toxicity or adverse effects concerns. Thus, a drug useful for treating emphysema without the toxicity problems of ATRA would be highly desirable.
The current invention is directed to methods of treating or preventing emphysema, pharmaceutical compositions suitable for the treatment or prevention of emphysema and methods for delivering formulations into the lung of a mammal suffering from emphysema.
More generally, the invention encompasses the use of 13-cis-retinoic acid to treat or prevent certain chronic obstructive airway disorders, particularly chronic obstructive pulmonary disease including chronic bronchitis, emphysema and asthma in mammals, especially humans that smoke or smoked cigarettes. In a preferred embodiment, the invention encompasses the treatment or prevention of panlobar emphysema, centrilobular emphysema or distal lobular emphysema in mammals using non-toxic and therapeutically effective doses of 13-cis-retinoic acid.
In one embodiment, the present invention encompasses the use of 13-cis-retinoic acid for treating or preventing emphysema. Further, the instant invention encompasses the use of pharmaceutical compositions of 13-cis-retinoic acid to treat or prevent emphysema. Moreover, the current invention encompasses the use of electrohydrodynamic aerosol devices, aerosol devices and nebulizers to deliver formulations of 13-cis-retinoic acid into the lung of a mammal suffering from or at risk of emphysema.
The invention encompasses the systemic use as well as the local use of 13-cis-retinoic acid or both in combination. Either or both can be achieved by the oral, mucosal or parenteral modes of administration. As mentioned above, means of delivering 13-cis-retinoic acid directly into the lung by nebulizer, inhaler or other known delivery devices are encompassed by the invention.
A method for treating emphysema by combining 13-cis-retinoic acid with one or more additional therapies such as smoking cessation (where appropriate) bronchodilators, antibiotics, oxygen therapy and the like is also encompassed by the invention.
In another aspect, the current invention encompasses methods for preventing emphysema in a human at risk of emphysema through administration of an amount of 13-cis-retinoic acid, or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof, that is sufficient to prevent emphysema. In a final aspect, the current invention encompasses pharmaceutical compositions for preventing emphysema in a human at risk of emphysema through administration of a amount of 13-cis-retinoic acid, or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof in a pharmaceutically acceptable carrier, that is sufficient to prevent emphysema.
As used herein, the term xe2x80x9cmammalxe2x80x9d includes human. The terms xe2x80x9chumanxe2x80x9d and xe2x80x9cpatientxe2x80x9d are used interchangeably herein.
As used herein, the term xe2x80x9ctreating emphysemaxe2x80x9d means alleviating, ameliorating, reducing, or relieving at least one symptom of emphysema. Symptoms of emphysema include, but are not limited to chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity, wheezing, abnormal enlargement of the airspaces distal to the terminal bronchioles and destruction of their walls.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic organic or inorganic bases. Suitable organic bases include, but are not limited to, lysine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable inorganic bases include, but are not limited to, alkaline and earth-alkaline metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
As used herein xe2x80x9cpro-drugxe2x80x9d refers to any compound which releases an active drug in vivo when such a compound is administered to a mammalian subject. Pro-drugs can be prepared, for example, by functional group modification of a parent drug. The functional group may be cleaved in vivo to release the active parent drug compound. Pro-drugs include, for example, compounds in which a group that may be cleaved in vivo is attached to a hydroxy, amino or carboxyl group in the active drug. Examples of pro-drugs include, but are not limited to esters (e.g., acetate, methyl, ethyl, formate, and benzoate derivatives), carbamates, amides and ethers. Methods for synthesizing such pro-drugs are known to those of skill in the art.
Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with preferred embodiments, it should be understood that it is not intended to limit the invention to these preferred embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.